Is IRF3 p.Arg86Cys (c.256C>T) pathogenic?

IRF3 p.Arg86Cys (c.256C>T) is classified Uncertain significance in IRF3 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-11-20). AlphaMissense: likely pathogenic (0.7308); Very rare (popmax 0.00333%, amr).

How common is IRF3 p.Arg86Cys (c.256C>T) in the general population?

IRF3 p.Arg86Cys (c.256C>T) is very rare (popmax 0.00333%, amr) (gnomAD).

What do computational predictors say about IRF3 p.Arg86Cys (c.256C>T)?

AlphaMissense predicts likely pathogenic (score 0.7308) — an in-silico prediction, not a clinical call.

IRF3 p.Arg86Cys

c.256C>T · VCV3530025

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.7308 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00333%, amr)

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.7308	likely pathogenic
REVEL	0.744	pathogenic-leaning
SaProt	LLR -4.46	tolerated
⇒ AlphaMissense and REVEL call this damaging; SaProt does not.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · G>T here scores Δ0.45 · evaluated, not missing
Constraint at this position
Conservation	phyloP 4.4	phastCons 1
Regional constraint	o/e 0.90	unconstrained · MANE · 5,187 bp · p 0.022 · regional, not allelic
Overall
CADD	29.5	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00333% Admixed American · 2/60,018 alleles

Filtering AF 0.000553% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000207%

Overall 0.000342% 5/1,461,884 alleles · very rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00333%	30,009
Remaining individualsnot grpmax-eligible	0.0016%	62,510
European (non-Finnish)	0.000169%	590,019

Rarity supports pathogenicity (ACMG PM2); frequency above a disease-specific BA1/BS1 threshold argues against it. A variant frequent in one ancestry group can be near-absent in others, so a single global figure can mislead.

Variant & gene context

Gene: IRF3
Protein: p.Arg86Cys
Coding: c.256C>T
MANE Select: NM_001571
Type: single nucleotide variant
Location: chr19:49663424 (GRCh38)
Gene constraint: LOEUF 0.949 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 81.58 · 18 PDB
Residue 86: a DNA-binding region

Full IRF3 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

IRF3 p.Arg86His Uncertain significance ★ ⚠ same residue
IRF3 p.Arg213Cys Uncertain significance ★★ ⚠ same type
IRF3 p.Arg96Trp Uncertain significance ★★ ⚠ same type
IRF3 p.Asn28Lys Uncertain significance ★★ ⚠ same type
IRF3 p.Asp45Asn Uncertain significance ★★ ⚠ same type
IRF3 p.Gln15Arg Uncertain significance ★★ ⚠ same type
IRF3 p.Leu344Phe Uncertain significance ★★ ⚠ same type
IRF3 p.Ser97Arg Uncertain significance ★★ ⚠ same type

Built on 18 open, versioned datasets — ClinVar, gnomAD, AlphaMissense, REVEL, ClinGen & more — plus Sugi Variant's own cross-source analysis. Source data 2026-01–2026-10, ClinVar 2026-10. Full sources & versions →

Cite Sugi Variant

Gür T. Sugi Variant: A Deterministic Per-Variant Germline Reference from a Knowledge Graph for Humans and AI Agents. 2026. doi:10.5281/zenodo.21509445. This variant: https://sugi.bio/variant/irf3-p-arg86cys (accessed [today's date]).

Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown